The World Health Organization estimates that over 40 million people are infected with HIV/AIDS. Emerging resistance to current antiretroviral treatments accentuates the need for the developing of new drugs aimed at targets other than the traditional ones, protease or reverse transcriptase. Among the new classes of drugs, the HIV viral entry inhibitors are especially promising since they target protein complexes involved in viral membrane fusion. BMS-806, a small molecule drug candidate that binds to the HIV-1 envelope protein gp120, has shown to be a potent and specific HIV-1 viral entry inhibitor. Despite being already in clinical trials, a complete understanding of the mechanism of action of BMS-806 and its analogs is still lacking. This proposal is designed to gain a fundamental understanding of the molecular mechanism of binding of BMS- 806 to the envelope glycoprotein gp120 in order to identify the chemical and structural determinants of its antiviral activity. The proposed studies will provide fundamental information for the design of new small molecule scaffolds that contain the essential binding characteristics for viral entry inhibition. The creation of a cocktail of viral entry inhibitors will slow down the onset of drug resistance. [unreadable] [unreadable] [unreadable]